Sci. Aging Knowl. Environ., 3 March 2004
Vol. 2004, Issue 9, p. nf25
[DOI: 10.1126/sageke.2004.9.nf25]

NEWS FOCUS

Copper Stopper

Obliterating a metal transporter immortalizes a fungus

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/2004/9/nf25

Copper in mitochondria tarnishes a fungus, according to new work. The study suggests that a dearth of the metal forces the organism to switch to a metabolic strategy that extends life. The results add to the evidence that fine-tuning metabolism can minimize cellular damage and delay death, although the organism sacrifices robust growth for that benefit.

Key differences set the fungus Podospora anserina apart from some of its cousins. Whereas the common lab inhabitant--baker's yeast--lives as individual cells, Podospora forms a mycelium, a multicelled structure consisting of branched filaments that resembles a microscopic shrub. Mycelia in some fungal species are immortal, but Podospora mycelia reach the mycological equivalent of old age. They eventually stop growing and cease sprouting new filaments. Researchers had previously found that different genetic lines of Podospora age at different rates. For instance, a mutant called GRISEA lives twice as long as normal; the mutation hampers the activity of genes that enable cells to take up copper and distribute it within the cell. The normal grisea gene activates another gene called PaCox17, whose product helps deliver copper to mitochondria. In the new work, Stumpferl and colleagues investigated whether hampering PaCox17 extends life.

The researchers removed the gene from Podospora cells and grew them into mycelia. The cultures aged much more slowly than did those that retain the gene. Furthermore, even GRISEA mutants die after 90 days, but cultures without PaCox17 were still going strong after 320 days. Previous studies revealed that Podospora endures when it exploits an unusual energy-manufacturing scheme. Rather than depending on cytochrome oxidase, a protein that uses copper as it helps produce ATP, these strains recruit an alternate shuttle called AOX1 that doesn't use the metal. Additional experiments suggest that Podospora mycelia without PaCox17 make the same switch. They generate larger than normal amounts of AOX1 and carry more of the protein than do GRISEA mutants. Adding a molecule that inhibits cytochrome oxidase did not block oxygen uptake by mitochondria, a gauge of the organelles' activity, but exposing the fungus to an AOX1 blocker slowed oxygen absorption.

Cytochrome oxidase generates more reactive oxygen species (ROS) than does AOX1, say the authors, so PaCox17-deficient cultures might live long because they minimize oxidative damage. Although copper helps generate ROS in mitochondria, it helps destroy them outside the mitochondria by activating a detoxifying enzyme called superoxide dismutase. Podospora that lack PaCox17 perhaps live longer than GRISEA mutants do because the copper deficiency is restricted to mitochondria, quelling cytochrome oxidase activity but maintaining superoxide dismutase activity. Plants also have the AOX pathway, which they use to optimize metabolism during stressful conditions such as drought or cold, says molecular biologist Lee McIntosh of Michigan State University in East Lansing. But plant researchers haven't delved into the pathway's effects on aging. Studies such as this one provide new insights into that phenomenon, he says, but long life might come at a steep price. The AOX1 pathway drastically reduces energy production, and organisms that use it grow sluggishly, McIntosh adds; Podospora might live long because it's in slow motion. Future work should reveal how rerouting copper keeps a fungus golden.


March 3, 2004
  1. S. W. Stumpferl, O. Stephan, H. D. Osiewacz, Impact of a disruption of a pathway delivering copper to mitochondria on Podospora anserina metabolism and life span. Eukaryot. Cell 3, 200-211 (2004). [Abstract/Free Full Text]
Citation: R. J. Davenport, Copper Stopper. Sci. Aging Knowl. Environ. 2004 (9), nf25 (2004).








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